Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Allografting

Transplantation of allogeneic CD34-selected stem cells after fludarabine-based conditioning regimen for children with mucopolysaccharidosis 1H (M. Hurler)

Bone Marrow Transplantation volume 35, pages 265–269 (2005)Cite this article

Summary:

Hurler syndrome (MPS1H) is a progressive inborn error of mucopolysaccharide metabolism leading to premature death. Allogeneic hematopoietic cell transplantation (HCT) can achieve stabilization and improve long-term survival. However, large studies have shown that preparative regimen-related toxicity (RRT) and graft failure rates have been relatively high. We transplanted five Hurler children with a fludarabine-based conditioning regimen, consisting of fludarabine/busulphan/ATG for matched family donor (MFD), with the addition of melphalan for mismatched family donor and matched unrelated donor (MUD) transplantations. Median age at HCT was 27 months (range 10–36). The source of stem cells was bone marrow in one MFD and CD34-selected PBSC in four patients. Median CD34+ cell dose was 25 × 106/kg (range 11.5–54). No RRT >grade II was observed. All patients are surviving at a median of 32 months (range 14–41) and show sustained donor engraftment with 3/5 having full donor chimerism, and 2/5 mixed chimerism (>85%). We conclude that this regimen is feasible and has low toxicity in Hurler children. In combination with high doses of CD34+ selected cells (>10 × 106/kg) and donor lymphocyte infusions, stable engraftment could be achieved in unrelated and mismatched related transplantations.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Beck M . Variable clinical presentation in lysosomal storage disorders. J Inherit Metab Dis 2001; 24 (Suppl 2): 47–51.

    Article  PubMed  Google Scholar 

  2. Peters C, Balthazor M, Shapiro EG et al. Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome. Blood 1996; 87: 4894–4902.

    CAS  PubMed  Google Scholar 

  3. Peters C, Shapiro EG, Anderson J et al. Hurler syndrome: II. Outcome of HLA-genotypically identical sibling and HLA-haploidentical related donor bone marrow transplantation in fifty-four children. The Storage Disease Collaborative Study Group. Blood 1998; 91: 2601–2608.

    CAS  PubMed  Google Scholar 

  4. Peters C, Shapiro EG, Krivit W . Neuropsychological development in children with Hurler syndrome following hematopoietic stem cell transplantation. Pediatr Transplant 1998; 2: 250–253.

    CAS  PubMed  Google Scholar 

  5. Grewal SS, Krivit W, Defor TE et al. Outcome of second hematopoietic cell transplantation in Hurler syndrome. Bone Marrow Transplant 2002; 29: 491–496.

    Article  CAS  PubMed  Google Scholar 

  6. McDonald GB, Slattery JT, Bouvier ME et al. Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood 2003; 101: 2043–2048.

    Article  CAS  PubMed  Google Scholar 

  7. Chun HG, Leyland-Jones B, Cheson BD . Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies. J Clin Oncol 1991; 9: 175–188.

    Article  CAS  PubMed  Google Scholar 

  8. Keating MJ, O'Brien S, Lerner S et al. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood 1998; 92: 1165–1171.

    CAS  PubMed  Google Scholar 

  9. Nieto Y, Vaughan WP . Pharmacokinetics of high-dose chemotherapy. Bone Marrow Transplant 2004; 33: 259–269.

    Article  CAS  PubMed  Google Scholar 

  10. Schmidt J, Fleissner S, Heimann-Weitschat I et al. Effect of corticosteroids, cyclosporin A, and methotrexate on cytokine release from monocytes and T-cell subsets. Immunopharmacology 1994; 27: 173–179.

    Article  CAS  PubMed  Google Scholar 

  11. Scott HS, Bunge S, Gal A et al. Molecular genetics of mucopolysaccharidosis type I: diagnostic, clinical, and biological implications. Hum Mutat 1995; 6: 288–302.

    Article  CAS  PubMed  Google Scholar 

  12. Yogalingam G, Guo XH, Muller VJ et al. Identification and molecular characterization of alpha-L-iduronidase mutations present in mucopolysaccharidosis type I patients undergoing enzyme replacement therapy. Hum Mutat 2004; 24: 199–207.

    Article  CAS  PubMed  Google Scholar 

  13. Guffon N, Souillet G, Maire I et al. Follow-up of nine patients with Hurler syndrome after bone marrow transplantation. J Pediatr 1998; 133: 119–125.

    Article  CAS  PubMed  Google Scholar 

  14. Vassal G, Fischer A, Challine D et al. Busulfan disposition below the age of three: alteration in children with lysosomal storage disease. Blood 1993; 82: 1030–1034.

    CAS  PubMed  Google Scholar 

  15. Jacobson P, Park JJ, Defor TE et al. Oral busulfan pharmacokinetics and engraftment in children with Hurler syndrome and other inherited metabolic storage diseases undergoing hematopoietic cell transplantation. Bone Marrow Transplant 2001; 27: 855–861.

    Article  CAS  PubMed  Google Scholar 

  16. Krivit W, Aubourg P, Shapiro E, Peters C . Bone marrow transplantation for globoid cell leukodystrophy, adrenoleukodystrophy, metachromatic leukodystrophy, and Hurler syndrome. Curr Opin Hematol 1999; 6: 377–382.

    Article  CAS  PubMed  Google Scholar 

  17. Finke J, Bertz H, Schmoor C et al. Allogeneic bone marrow transplantation from unrelated donors using in vivo anti-T-cell globulin. Br J Haematol 2000; 111: 303–313.

    Article  CAS  PubMed  Google Scholar 

  18. Dalle JH, Wall D, Theoret Y et al. Intravenous busulfan for allogeneic hematopoietic stem cell transplantation in infants: clinical and pharmacokinetic results. Bone Marrow Transplant 2003; 32: 647–651.

    Article  CAS  PubMed  Google Scholar 

  19. Nguyen L, Fuller D, Lennon S et al. I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients. Bone Marrow Transplant 2004; 33: 979–987.

    Article  CAS  PubMed  Google Scholar 

  20. Sarosy G, Leyland-Jones B, Soochan P, Cheson BD . The systemic administration of intravenous melphalan. J Clin Oncol 1988; 6: 1768–1782.

    Article  CAS  PubMed  Google Scholar 

  21. Singhal S, Powles R, Treleaven J et al. Melphalan alone prior to allogeneic bone marrow transplantation from HLA-identical sibling donors for hematologic malignancies: alloengraftment with potential preservation of fertility in women. Bone Marrow Transplant 1996; 18: 1049–1055.

    CAS  PubMed  Google Scholar 

  22. Taha IA, Ahmad RA, Rogers DW et al. Pharmacokinetics of melphalan in children following high-dose intravenous injection. Cancer Chemother Pharmacol 1983; 10: 212–216.

    Article  CAS  PubMed  Google Scholar 

  23. Jacobsohn DA, Duerst R, Tse W, Kletzel M . Reduced intensity haemopoietic stem-cell transplantation for treatment of non-malignant diseases in children. Lancet 2004; 364: 156–162.

    Article  PubMed  Google Scholar 

  24. Staba SL, Escolar ML, Poe M et al. Cord-blood transplants from unrelated donors in patients with Hurler's syndrome. N Engl J Med 2004; 350: 1960–1969.

    Article  CAS  PubMed  Google Scholar 

  25. Ho VT, Weller E, Lee SJ et al. Prognostic factors for early severe pulmonary complications after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2001; 7: 223–229.

    Article  CAS  PubMed  Google Scholar 

  26. Ritchie DS, Seymour JF, Roberts AW et al. Acute left ventricular failure following melphalan and fludarabine conditioning. Bone Marrow Transplant 2001; 28: 101–103.

    Article  CAS  PubMed  Google Scholar 

  27. Reisner Y, Martelli MF . Tolerance induction by ‘megadose’ transplants of CD34+ stem cells: a new option for leukemia patients without an HLA-matched donor. Curr Opin Immunol 2000; 12: 536–541.

    Article  CAS  PubMed  Google Scholar 

  28. Lang P, Klingebiel T, Bader P et al. Transplantation of highly purified peripheral-blood CD34+ progenitor cells from related and unrelated donors in children with nonmalignant diseases. Bone Marrow Transplant 2004; 33: 25–32.

    Article  CAS  PubMed  Google Scholar 

  29. Kremens B, Basu O, Peceny R et al. Allogeneic CD34+-selected peripheral stem cell transplantation from parental donors in children with non-malignant diseases. Bone Marrow Transplant 2002; 29: 9–13.

    Article  CAS  PubMed  Google Scholar 

  30. Bader P, Klingebiel T, Schaudt A et al. Prevention of relapse in pediatric patients with acute leukemias and MDS after allogeneic SCT by early immunotherapy initiated on the basis of increasing mixed chimerism: a single center experience of 12 children. Leukemia 1999; 13: 2079–2086.

    Article  CAS  PubMed  Google Scholar 

  31. Bader P, Kreyenberg H, Hoelle W et al. Increasing mixed chimerism defines a high-risk group of childhood acute myelogenous leukemia patients after allogeneic stem cell transplantation where pre-emptive immunotherapy may be effective. Bone Marrow Transplant 2004; 33: 815–821.

    Article  CAS  PubMed  Google Scholar 

  32. Woodard P, Cunningham JM, Benaim E et al. Effective donor lymphohematopoietic reconstitution after haploidentical CD34+-selected hematopoietic stem cell transplantation in children with refractory severe aplastic anemia. Bone Marrow Transplant 2004; 33: 411–418.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We recognize the outstanding care provided by the nurses of the Mildred-Scheel Bone Marrow Transplantation unit of the Medical School, Hannover.

Author information

Authors and Affiliations

  1. Pediatric Hematology and Oncology, Children's Hospital, Hannover Medical University, Hannover, Germany

    L Grigull, A Beilken, M Schrappe, A Sander, M Stanulla, K Rehe, M Sauer, H Schmid, K Welte & K W Sykora

  2. Pediatric Metabolic Disease Section, Children's Hospital, Hannover Medical University, Hannover, Germany

    A Das & T Luecke

  3. Metabolic Laboratory, Department of Pediatrics, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Z Lukacs

  4. Institute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    A Gal

Authors
  1. L Grigull
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Beilken
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Schrappe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Luecke
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Sander
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Stanulla
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K Rehe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Sauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. H Schmid
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. K Welte
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Z Lukacs
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. A Gal
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. K W Sykora
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L Grigull.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grigull, L., Beilken, A., Schrappe, M. et al. Transplantation of allogeneic CD34-selected stem cells after fludarabine-based conditioning regimen for children with mucopolysaccharidosis 1H (M. Hurler). Bone Marrow Transplant 35, 265–269 (2005). https://doi.org/10.1038/sj.bmt.1704786

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1704786

Keywords

This article is cited by

Search

Advanced search

Quick links